1. Field of the Invention
The present invention relates to evaluation methods for evaluating susceptibility to multifactorial diseases in sexual differentiation disorders, a human estrogen receptor alpha (α) gene carrying single nucleotide polymorphisms (hereafter abbreviated as SNPs) associated with the multifactorial diseases, DNAs containing nucleotides at the SNPs, and diagnostic markers composed of the DNAs.
2. Description of the Related Art
Sexual differentiation proceeds under the temporally and spatially strict control based on the heredity program that specifies the expression of the sexual phenotype of a person, resulting in occurrence of sexual phenotypes, such as gonad formation, formation of sexual ducts and external genitalia, appearance of the secondary sex characteristics, and gametogenesis. This sexual differentiation process is characterized by the followings:    (1) In gonad formation and external genitalia differentiation, precursors common to both sexes are formed during early developmental stages and then these precursors differentiate into different gonads and external genitalia according to the genetic sex.    (2) In sexual duct formation, organs of both sexes are formed in early developmental stages, and then only sexual ducts that match the genetic sex grow.    (3) Reproductive cells, the only cells passed on to the next generation, develop.When a problem occurs somewhere in the proceeding process of this hereditary program, a sex differentiation disorder develops.
Among sex differentiation disorders, clinically, abnormalities of the external genitalia are common in boys. Many genes involved in abnormalities of the external genitalia in boys have been identified through gene analyses in human patients and studies with laboratory animals.
Abnormalities in these genes induce diseases of the external genitalia via either of hypoplasia of fetal testes (broadly divided into undifferentiated gonadal dysplasia and disorders of fetal testis differentiation), disorders of androgen production (broadly divided into disorders of cholesterol biosynthesis and disorders of steroid hormone synthetase), impaired androgen effect, or hypoplasia of the precursor of the external genitalia.
However, these diseases include multifactorial diseases which are not inherited in a Mendelian fashion and whose onset is suggested to be influenced not only by hereditary factors but also environmental factors. Typical examples of such diseases include micropenis, cryptorchidism, hypospadias, etc. In addition, defective spermatogenesis is considered to be caused by endocrine disruptors.
Additionally, when those females/girls carrying the same polymorphisms as above have multifactorial diseases (for example, premature thelarche, pubertas praecox, and endometriosis) ascribed to endocrine disruptors, their susceptibility to endocrine disruptors are considered to have increased.